Multi component controlled release system for oral care, food products, nutraceutical, and beverages

ABSTRACT

The present invention relates to an improved controlled release system that can encapsulate different flavors, sensory markers, and active ingredients, or combinations of flavors, sensory markers and various active ingredients and release multiple active ingredients in a consecutive manner, one after the other. The controlled delivery system of the present invention is substantially free-flowing powder formed of solid hydrophobic nanospheres that are encapsulated in a moisture sensitive microspheres. The flavors, and active ingredients encapsulated in the hydrophobic nanospheres, in the water sensitive microsphere, or in both the nano and the microsphere. The flavors and active ingredients encapsulated in the nanospheres can be the same or different from those encapsulated in the microspheres. The encapsulation of different flavors or active agents in the various components of the system, such as nanospheres and microspheres, provides flavor transition (change in flavor character) during the use of the products. The controlled release system of the present invention enhances the stability and bioavailability of wide range of flavors, sensory markers, and other active ingredients, prolong their residence time in the oral cavity, control their release characteristics, and prolong the sensation of flavors and other sensory markers in the mouth to provide long lasting organoleptic perception or long lasting mouthfeel. The invention further relates oral care, food products, and beverages comprising the controlled release system of the present invention.

CROSS REFERENCE TO RELATED APPLICATION

This patent application is a continuation in part of U.S. applicationSer. No. 09/696,148, filed Oct. 25, 2000, entitled “MulticomponentBiodegradable Bioadhesive Controlled Release System for Oral CareProducts,” the contents of which are incorporated by reference into thisapplication.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to multi component controlled releasesystem that can be incorporated in oral care products, nutraceutical,food products and beverages to effectively encapsulate one or multipleactive ingredients and sensory markers (i.e., flavors, cooling agents,sweeteners, etc.) and release multiple active ingredients in aconsecutive manner, one after the other. The controlled release systemof the present invention enhances the stability and bioavailability ofwide range of flavors, sensory markers, and other active ingredients,prolongs their residence time in the oral cavity, controls their releasecharacteristics, and prolongs the sensation of flavors and sensorymarkers in the mouth to provide long lasting organoleptic perception orlong lasting mouthfeel. The invention further relates to oral care, foodproducts, and beverages comprising the controlled release system of thepresent invention.

2. Description of the Related Art

Extensive effort has been directed in recent years towards controllingthe release characteristics of various active ingredients flavors andsensory markers to prolong product shelf life and to prolong thesensation in the mouth during consumption of food products andbeverages. Various methods and compositions have been described forproviding enhanced stability and better control of the release of activeingredients and flavors in food products.

Spray drying, accounts for the majority of commercial encapsulatedmaterials in food products. The spray drying encapsulation process isrelatively simple, economical, and easily scaled to large productionvolumes. A major benefit of spray drying encapsulation is the broadrange of actives and sensory markers which can be encapsulated. Theseactives include oil-soluble flavors, water-soluble compounds, naturalextracts, single component flavor compounds, as well as complexcompounded flavors having both water- and oil-soluble components.

U.S. Pat. No. 3,971,852 discloses the use of modified starch, gums andother natural hydro-colloids with lower molecular weight polyhydroxycompounds to yield a glassy cellular matrix with encapsulated oil at amaximum of 80 volume %. This system forms a shell surrounding the oilflavoring but is limited to lipophilic flavoring agents.

U.S. Pat. No. 4,532,145 describe a process and composition in which avolatile flavorant is fixed by spray drying from a carrier solution madeup of 10-30% of a low molecular weight component such as a sugar or anedible food acid with the balance of solids being a maltodextrincarbohydrate in the amount of 70-90%.

U.S. Pat. No. 5,124,162 discloses a carrier mixture composed of mono-and disaccharides (22-45%), maltodextrins (25-50%), and a high molecularweight carbohydrate such as gum arabic, gum acacia or chemicallymodified starch (10-35%) to which flavoring agents are added and thesubsequent solution spray dried to yield a free flowing powder with abulk density of 0.50 g/cc.

U.S. Pat. No. 4,859,377 describes the use of amylose-containingpregelatinized starch to encapsulate entomopathogens, thereby protectingsuch biocontrol agents from environmental degradation and also promotinginfection of target pests. The encapsulation is effected in an aqueousdispersion of the pregelatinized starch: for dry, granular products, thestarch solids content of the dispersion is 25-40%; for sprayable liquidproducts, chemically degraded starch is used at a solids content of1-10%.

U.S. Pat. No. 4,911,952 discloses chemical biological agents to beencapsulated are blended into an aqueous dispersion of an unmodifiedstarch comprising about 5% to about 25% by weight amylose. Thedispersion, having an initial starch solids content of about 20% byweight, is characterized by completely disrupted starch granules andcompletely disassociated amylose molecules that are not significantlydepolymerized. Subsequent drying is accomplished by reassociation of theamylose molecules which converts the dispersion into a protective matrixand binds the agents within the interstices of the reassociating starchchains. Rate of release of agents to the environment can be altered byvarying the proportion of amylose in the starch. Encapsulation ofbiologically active compositions provides protection against degradativeenvironmental conditions, improves safety in handling, and slows therelease of such compounds to the surrounding medium.

U.S. Pat. No. 5,183,690 discloses biologically active agents to beencapsulated are continuously blended with a starchy material and water,subjected to high-shear mechanical action at a temperature above thegelatinization temperature of starch, and continuously recovered as aninsolubilized matrix of starch that entraps discontinuous domains of theagent. Alternatively, the core material to be encapsulated is added andblended with the aqueous dispersion of starch after the starch and waterhave been subjected to an elevated temperature sufficient to gelatinizethe starch. Rate of release of agents to the environment can becontrolled by pre-selecting a set of conditions related to variousprocessing parameters. Encapsulation of biologically active compositionsprovides protection against degradative environmental conditions,improves safety in handling, and slows the release of such compounds tothe surrounding medium.

U.S. Pat. No. 5,506,353 discloses particulate flavor compositioncomprising a flavor oil fixed in a particulate low cariogenic matrix ofhydrogenated starch hydrolysate and a maltodextrin having a dextroseequivalent value of less than 20. A process for the encapsulation of aflavor oil comprising forming a homogeneous mixture of the flavor oilwith (a) from about 40 to about 85 percent by weight of a particulatepolyol consisting of hydrogenated starch hydrolysate, (b) from about 10to about 30 percent by weight of a maltodextrin having a dextroseequivalent of less than 20, (c) an emulsifier and water, andspray-drying the resultant mixture to form a particulate product of fromabout 0.15 to about 0.85 g/cc bulk free flow density. Methods to confer,enhance or modify the flavor properties of a consumable edible materialwhich comprises adding thereto the particulate flavor compositiondefined above; and methods to confer, enhance or modify the flavorproperties of a tooth-paste base which comprises adding thereto theparticulate flavor composition defined above are described.

An alternative process for encapsulation of active ingredients andsensory markers for food products is melt extrusion. In this process, amelting system, i.e. an extruder, is employed to form the carrier meltin a continuous process. The encapsulated flavor is either admixed orinjected into the molten carbohydrate carrier.

U.S. Pat. No. 2,809,895 describes a process for encapsulation of anessential oil, such as lemon, lime or grapefruit oils, in a matrixcomprising corn syrup, antioxidant and dispersing agent. The essentialoil, antioxidant and dispersing agent are added to the corn syrup, theresultant mixture is heated to 85 degree-125 degree C. and agitated orextruded to form an emulsion in pellet form, and the resulting particlesare washed with a solvent and finally dried.

Similarly, in U.S. Pat. No. 3,922,354, Galuzzi et al. disclose the useof high-shear mixing to incorporate active agents into low-water,high-solids matrices prepared from partially gelatinized unmodifiedstarches. Additives such as modified dextrins, mixtures of mono- anddiglycerides, toasted cereal solids, and coloring agents are used tocontrol the release of active agents.

U.S. Pat. No. 4,232,047 teaches the preparation of a food supplementconcentrate of an ingestible agent encased as a dispersed microphase ina matrix encapsulating medium, such as starch, protein, flour, modifiedstarch, gum, or mixtures thereof. The concentrate is prepared by mixingthe ingestible agent and the encapsulating medium with limited water toconvert the mixture, under applied extrusion pressure and controlledheat. The protein exemplified is gelatin.

U.S. Pat. No. 4,230,687 discloses the application of shearing stress,vigorous mechanical working, and heat to distribute active agent into anenveloping matrix of chemically modified starches, gums, and proteins inthe presence of a limited quantity of water. Proteins are used forslow-release matrices; modified starches are used for rapid release.

U.S. Pat. No. 4,420,534 describes the use of a matrix compositionconsisting of 10 to 30 wt % of a low molecular weight component chosenfrom a series of mono- or disaccharides, corn syrup solids, or organicacid with the balance of the mixture being maltodextrin. The matrix baseis dry blended with an anhydrous liquid flavoring component and meltedin a single screw extruder to yield a solid matrix characterized as aglass with a glass transition temperature >40° C.

U.S. Pat. No. 4,689,235 discloses an extrudable encapsulation matrixcomposition having improved loading capacity for oils, flavors,fragrances, agricultural chemicals, insecticides, drugs, etc. The matrixcomprises a maltodextrin and hydrogen octenylbutanedioate amylodextrinor equivalent.

U.S. Pat. Nos. 4,610,890 and 4,707,367 disclose a solid essential oilflavor composition having a high essential oil content and a process forpreparing the product are disclosed, the process involving preparationof a heated or cooked aqueous mixture of a sugar and starch hydrolyzatetogether with an emulsifier. A selected essential oil or otheroil-soluble flavor is combined and blended with a mixture in a closedvessel under controlled pressure conditions to form a homogeneous melt,the melt being extruded into a relatively cool solvent, dried andcombined with a selected anticaking agent to produce the stable,relatively non-hygroscopic particulate flavor composition of theinvention. The selected quantity of essential oil flavor blended intothe homogeneous melt being sufficient to yield about 12 to 35% by weightof essential oil in the encapsulated solid particulate composition.During the process, encapsulation efficiency is maintained preferably ator above about 60%, more preferably above about 70% and most preferablyabove about 75 to 80%. Also, the cook temperature for the process ispreferably maintained at or below a maximum of about 126 degree C.

U.S. Pat. Nos. 4,610,890 and 4,707,367 describe a process for preparinga solid essential oil composition having a high content of the essentialoil, which composition is prepared by forming an aqueous solutioncontaining a sugar, a starch hydrolysate and an emulsifier. Theessential oil is blended with the aqueous solution in a closed vesselunder controlled pressure to form a homogeneous melt, which is thenextruded into a relatively cold solvent, dried and combined with ananti-caking agent.

U.S. Pat. No. 4,929,447 discloses method and composition for protectingan active ingredient and providing controlled release therefore,especially in a chewing gum composition, which includes a high molecularweight polyvinyl acetate blended with a hydrophobic plasticizer whichforms a film with the high molecular weight polyvinyl acetate in theabsence of an added solvent therefore. The active ingredient, such asthe artificial sweetener aspartame, is blended into the encapsulatingcomposition as, for example, by melt blend which can then be cooled to asolid and ground into particulate. The encapsulated active ingredientcan then be used in a composition for ingestion by a human in the formof, for example, a chewing gum with extended shelf life and highlycontrolled release of the active ingredient.

Encapsulation of components in a grindable, glassy carbohydrate matrixis disclosed in U.S. Pat. Nos. 5,009,900 and 5,087,461 and U.S. Pat.Nos. 5,972,404 and 6,004,594. In U.S. Pat. Nos. 5,009,900 and 5,087,461volatile and/or labile components, such as vitamins or flavoringcomponents, are encapsulated in extruded glassy matrices comprising awater-soluble, chemically-modified starch having a dextrose equivalentnot greater than about 2, a maltodextrin having a dextrose equivalent inthe range of from about 5 to about 15, corn syrup solids or apolydextrose having a dextrose equivalent in the range of from about 21to about 42, and a mono- or disaccharide.

U.S. Pat. Nos. 6,468,568 and 6,436,453 disclose a mineral or vitaminfortification ingredient which does not deleteriously affectpalatability and appearance of foods is obtained by encapsulation of themineral or vitamin in a grindable, glassy matrix composition. The glassymatrix composition includes an oligosaccharide, such as beta-2-1fructofuranose materials, preferably fructooligosaccharides (FOS) andinulin, which not only forms a glassy matrix, but also beneficiallyincreases the fiber content of the food. At least one edible oil isincluded in the encapsulating composition to prevent substantial adverseinteraction between the mineral or vitamin encapsulant and theglass-forming oligosaccharide matrix material, and to achieve controlledrelease of the encapsulant from the glassy matrix. A method forencapsulating a mineral or vitamin in a glassy matrix is describedcomprising: a. admixing an encapsulant component comprising at least onemineral or vitamin with an edible oil to obtain a slurry wherein said atleast one mineral or vitamin is encapsulated by said oil, b. admixingsaid slurry with a melt comprising at least one molten glass-formingoligosaccharide matrix component to obtain a molten blend, and c.cooling the molten blend to encapsulate the oil encapsulated mineral orvitamin in a glassy matrix.

U.S. Pat. Nos. 5,897,897, 6,187,351, and 6,416,799 disclosecarbohydrate-based glassy matrices which are stable in the glassy stateat ambient temperatures may be prepared by the use of aqueousplasticizers with melt extrusion. Such glassy matrices are useful forthe encapsulation of encapsulates, in particular, flavoring agents.

Coacervation is another encapsulation technology that was commercializedin the 1950s, yields that has found wide usage in the pharmaceutical,fragrance and specialty products industries. However the relatively highprocess costs, sensitive multi-step batch process, regulations limitingthe number of polymeric agents which can be used in food preparations,and the difficulty in dealing with encapsulates having both aqueous andlipid solubility properties has drastically limited the application ofcoacervation for flavor encapsulation in the food industry. A generaldiscussion of these issues is provided by R. Versic, “Coacervation forFlavor Encapsulation,” in Flavor Encapsulation, American ChemicalSociety Symposium Series #370, S. Risch and G. Reneccius, Eds., Chapter14, 1988, which is incorporated herein by reference. Coacervationmicrocapsule systems can be generated in the form of simple coacervates,which are derived from a single polymer species in solution. Complexcoacervates, which require the interaction of two distinct andoppositely charged polymer species, are also well characterized.

U.S. Pat. No. 3,962,463 discloses the encapsulation of flavoringredients in gelatin waxes, polyethylene and the like followed by thedepositing of the encapsulated flavor particles on the surface of thechewing gum. U.S. Pat. No. 4,217,368 discloses the controlled release ofa (second) sweetener which is dispersed in, enveloped by, trapped in andotherwise protected by the gum base. A first sweetener, which isrelatively unprotected, provides an initial burst of flavor. U.S. Pat.No. 4,259,355 discloses a hydrolytically releasable flavor oil entrappedin gelatine, dextrin, gum acacia or modified food starch with the aid ofa hydroxypropylcellulose solid suspending agent.

U.S. Pat. No. 4,230,687 discloses the encapsulation of flavoring agentin a polymeric medium using rigorous and intimate conditions ofmechanical shear to mix the flavoring agent with the encapsulatingmedium. The flavoring agent is gradually released from the encapsulatingmatrix at a rate dependent upon the rate of hydration of the matrix,which in turn depends upon the particular matrix used. The polymericmatrix may be derived from natural substances such as casein, a gelatin,modified starches, gums and related materials.

Complex coacervation encapsulation, which yields oil droplets surroundedby a chemically crosslinked polymer film has been utilized for theencapsulation of cinnamon oil in chewing gums as disclosed in U.S. Pat.No. 5,266,335.

U.S. Pat. No. 5,418,010 discloses a microencapsulation process in whicha solid or liquid core material is dispersed in a protein slurry, isheated to create a protein melt and then denatured to bring aboutencapsulation of the core material and the product of that process.

U.S. Pat. No. 6,428,827 discloses methods and compositions for improvingthe flavor duration in chewing gum. In a preferred form, the presentinvention provides matrix compositions comprising ahydroxypropylcellulose cross-linked with a multi-functional carboxylateto yield a matrix having lower water solubility than the originalcellulosic material. This matrix may be ground up, have a flavorincorporated therein and used in gum compositions in which itfacilitates a prolonged release of the flavoring.

Coating or fat coating is another encapsulation technique that has beenemployed. Conventionally, such fat coatings are applied via a fluidizedbed technique. This technique suffers from serious shortcomings, such asexposure of the active agent to a vigorous air stream that will resultin that significant active agents may either volatilize or oxidize undersuch conditions. This air contacting may occur over a long time periodas the rate of fat addition must often be slow, as it is determined bythe heat load the air stream can carry away. This also limits theoverall productivity of fluid-bed techniques, which in turn influencesprocessing costs and ultimately commercial utility. In addition, theprotection afforded by fat coatings applied as described above, or usingany method, may be easily lost when the fat-coated particle is exposedto temperatures above the melting point of the fat.

U.S. Pat. No. 3,976,794 shows sweetened coconut products coated with apowdered sugar containing particles of sugar coated in edible fat. U.S.Pat. Nos. 3,949,094 and 3,949,096 show a process for preparing variousflavorings, colorants, and flavor enhancers coated with various fats andemulsifiers, the process comprising spraying condiments which areintercepted by a second spray of certain edible coating materials.

In U.S. Pat. No. 4,765,996 polished rice or barley is enriched withnutrients which are fixed in and on the grain by coating an oil/fatand/or a wax on the grains, coating the same with a hydrophilicemulsifier and further coating them with a starch-based coating agent.

U.S. Pat. No. 5,500,223 discloses an encapsulation process employs anaqueous dispersion of silica having a particle size not substantiallygreater than 100 nm. An emulsion is formed by high shear mixing of thesilica dispersion with the material to be encapsulated and the emulsionis gelled. The process allows hydrophobic materials to be encapsulatedin structures which have a high loading of the material and a gooddegree of imperviousness in the presence of other materials such assurfactants and mineral oils. Using the process, hydrophobic materialssuch as flavors, fragrances and cosmetic ingredients can be encapsulatedfor delayed release in a wide variety of products.

U.S. Pat. No. 6,165,516 discloses a method for producing a chewing gumwith a controlled release of caffeine, as well as the chewing gum soproduced, is obtained by physically modifying caffeine's properties bycoating and drying. Caffeine is coated by encapsulation, partiallycoated by agglomeration, entrapped by absorption, or treated by multiplesteps of encapsulation, agglomeration, and absorption. The coatedcaffeine is then co-dried and particle sized to produce arelease-modified caffeine. When incorporated into the chewing gum, theseparticles are adapted to produce a fast release or a delayed releasewhen the gum is chewed.

U.S. Pat. No. 4,971,797 discloses stabilized sucralose complex in athermally stable composition by co-crystallization with a cyclodextrin.The resulting crystalline product may be comminuted to form particles ofdesired size for use as a sweetener component in place of or in additionto known sweeteners such as sucrose, saccharin and the like, in avariety of foods, comestibles, and oral medications. The preparation ofthe stabilized sucralose compositions of the present inventionconstitutes a molecular encapsulation of the sucralose within thecyclodextrin thereby protecting the sucralose from discoloration causedby heat.

Spray-chilling is another form of encapsulation practiced commercially.This process begins with mixing a liquid flavor into a molten fat tocreate a solution/dispersion. The resulting mixture is then atomizedinto a chamber where it is contacted with an air stream which is coolenough to cause the atomized droplets to solidify, thus forming a crudeencapsulated product. The major drawbacks of spray-chilling includefat/active-agent interactions, volatilization over time of lipid solublematerials, as well as loss of volatile materials during processing.

U.S. Pat. No. 5,064,669 discloses controlled release flowable flavoringpowders and processes and apparatus for preparing and using such agents,the processes comprising heating a high melting point encapsulating orenrobing material, such as a fat and/or wax and one or more emulsifiersto melt this starting material; mixing one or more water-containingflavor compositions with a texture conditioning agent; mixing the flavorcompositions and texture conditioning agent(s) with the molten fat orwax to obtain a homogeneous mixture in the form of an emulsion; andchilling the flavor composition-containing mixture to provide discreteparticles of solid encapsulated flavoring agent, together with theproducts so produced and methods for using same.

U.S. Pat. No. 6,245,366 discloses a fat-coated encapsulationcompositions may be prepared by: (i) mixing an active agent with amolten fat, to obtain a slurry, and (ii) cooling the slurry, to obtain asolid mass in which the active agent is dispersed in solid fat.

U.S. Pat. No. 6,328,988 discloses polymeric micelles for encapsulationof hydrophobic molecules are provided. Methods and formulations fordelivering hydrophobic molecules to a host via these micelles are alsoprovided. Methods of stabilizing liposomes or lipid based formulationsby addition of polymeric micelles are also provided.

Accordingly, there remains a need in the art to provide methods andcompositions using an efficient and economical process that can beincorporated in food products and beverages to effectively encapsulateone or multiple active ingredients and sensory markers (i.e., flavors,cooling agents, etc.), enhance their stability and bioavailability,control their release characteristics, prolong their sensation in themouth during consumption of food products and beverages to provide along lasting organoleptic perception or long lasting mouthfeel, andrelease multiple active ingredients in a consecutive manner.

SUMMARY OF THE INVENTION

The present invention relates to an improved controlled release systemthat can be incorporated in oral care, food products, and beverages thatcan effectively encapsulate one or more types of active ingredients,flavors, or combinations of flavors and various active ingredients torelease them one after the other in a consecutive manner or to providechange in flavor character. The controlled release system of the presentinvention can encapsulate a broad range of active ingredients andsensory markers (i.e., flavors, cooling agents, sweeteners, etc.), toenhance their stability and bioavailability, prolong their residencetime in the oral cavity, control their release characteristics, andprolong their sensation in the mouth during consumption of food productsand beverages to provide a long lasting organoleptic perception or longlasting mouthfeel.

The controlled release system of the present invention comprises solidhydrophobic nanospheres encapsulated in a moisture sensitivemicrosphere. The nanospheres are not individually coated by the moisturesensitive microspheres matrix, but are homogenously dispersed in thewater sensitive microsphere matrix. Various flavors and activeingredients can be incorporated in the hydrophobic nanosphere matrix, inthe water sensitive microsphere matrix, or in both the nano and microspheres matrices. The active ingredients, flavors, and sensory markersencapsulated in the nanospheres can be the same or different than thoseencapsulated in the microspheres. The nanosphere surface can include abioadhesive to improve the deposition and prolong the residence time ofthe nanospheres in the oral cavity. Alternatively, a bioadhesive polymercan be incorporated in the water sensitive microsphere matrix to createthe bioadhesive properties of the nanospheres.

The microspheres have an average sphere size in the range from about 20microns to about 100 microns. The nanosphere have an average sphere sizein the range from about 0.01 micron to about 5 microns and having amelting point in the range from about 30° C. to about 90° C. A firstflavor, or active ingredient can be encapsulated in a water sensitivemicrosphere and released upon exposure of the system to moisture(wetting the lips, in the mouth, and the like) and a second flavor, oractive ingredient can be encapsulated in the solid hydrophobicnanospheres and released over an extended period of time. In addition,the production of the controlled release system utilizes minimumprocessing steps and is efficient and economical.

The controlled release system of the present invention is a free-flowingpowder formed of solid hydrophobic nanospheres comprising flavors,sensory markers, and other various active ingredients, that areencapsulated in a moisture sensitive microsphere that can also containflavors, sensory markers, and other various active ingredients. Theactive ingredients encapsulated in the nanospheres can be the same ordifferent from those encapsulated in the microsphere. The controlledrelease system of the present invention is characterized by:

-   -   (i) protection of the active ingredients, as well as the        volatile constituents of flavors, during storage, until needed;    -   (ii) enhanced bioavailability of various active ingredients,        such as vitamins, biologically active agents, nutrients, and        others;    -   (iii) moisture triggered release of the flavors, and other        active ingredients that are encapsulated in the microsphere        water sensitive matrix, as well as, the nanospheres comprising        the same or other flavors, and active ingredients;    -   (iv) change in flavor character or other olfactory sensation in        response to moisture;    -   (v) prolonged release of flavors, and other active ingredients        that are encapsulated in the solid hydrophobic nanospheres, over        an extended period of time; and    -   (vi) long lasting organoleptic perception or long lasting        mouthfeel of flavors, sensory markers, sweeteners, and other        active ingredients.

The controlled release system of the present invention improves thestability of various active ingredients and flavors or flavoringredients in food products and beverages, protects them against thedevelopment of off-flavors and off odors such as protect citral andcitrus notes against oxidation, preventing the development ofoff-flavors and off odors, and increasing the shelf life of food andbeverage products.

The present invention also provides a method for producing the multicomponent controlled release system of the present invention comprisingthe steps of:

-   -   (i) incorporating the flavor, and other active ingredients into        the solid hydrophobic nanospheres;    -   (ii) forming an aqueous mixture comprising of one or more        flavor, and other active ingredients, the nanospheres, and a        water sensitive material, such as, starch derivatives, natural        gums, polyvinyl alcohol, proteins, hydrocolloids, or mixture of        thereof; and    -   (iii) spray drying the mixture to form a dry powder composition.

The invention further provides a process for producing the multicomponent controlled release system for food products and beverageincluding the flavors, and other active ingredients comprising the stepsof:

-   -   (i) heating one or more hydrophobic materials to a temperature        above the melting point of the materials to form a melt;    -   (ii) dissolving or dispersing a first flavor into the melt;    -   (iii) dissolving or dispersing a first one or more active        ingredients into the melt;    -   (iv) dissolving or dispersing a second flavor, active        ingredients, and moisture sensitive materials, such as, starch        derivatives, natural gums, polyvinyl alcohol, proteins,        hydrocolloids, or mixture of thereof, in the aqueous phase;    -   (v) heating the composition to above the melting temperature of        the hydrophobic materials; mixing the hot melt with the aqueous        phase to form a dispersion;    -   (vi) high shear homogenization of the dispersion at a        temperature above the melting temperature until a homogeneous        fine dispersion is obtained;    -   (vii) cooling the dispersion to ambient temperature; and    -   (viii) spray drying the emulsified mixed suspension to form a        dry powder composition.

Oral care, food products or beverages incorporating the multi componentsystem of the present invention that comprises different flavors orsensory markers in the nanospheres and the microspheres was found toprovide a perceivable flavor transition (change in flavor character) orchange in the organoleptic perception in response to moisture or changein the organoleptic perception, in response to moisture as well asprolonged flavor perception and mouthfeel. The multi component system ofthe present invention was found to extend the release rate of theflavors, sensory markers, and the active ingredients that wereencapsulated in the solid hydrophobic nanospheres over an extendedperiod of time to provide long lasting organoleptic perception or longlasting mouthfeel of flavors, sensory markers, sweeteners, and otheractive ingredients. In an alternate embodiment, a controlled releasecomposition for food products and beverages is formed of hydrophobicnanospheres incorporating flavors, sensory markers, and other activeagents.

The multi-component controlled release system of the present inventioncan comprise from about 1% to about 50% by weight of a hydrophobicmatrix, from about 1% to about 50% by weight of a water sensitivematrix, and from about 1% to about 50% by weight flavor, or other activeingredients.

The present invention addresses the foregoing need for food products andbeverages that provide special performance features to enhance productperformance and differentiate the product from that of the competitorsand provide long-term storage stability. The invention will be morefully described by reference to the following drawing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a controlled release system of thepresent invention.

FIG. 2 is an image showing bioadhesive nanospheres to HeLa culturedcells.

FIG. 3 is an image showing bioadhesive nanospheres of examples 1-4 toHeLa cultured cells.

FIG. 4 is a graph of the percent weight loss of citral from thechocolate comprising the neat citral oil vs. the percent weight loss ofcitral from the chocolate comprising encapsulated citral in thecontrolled release system of the present invention.

DETAILED DESCRIPTION

The present invention provides a method to enhance the performance offood products, beverages, and other oral care compositions. Theinvention relates to a controlled release system that can provide aperceivable flavor transition (change in flavor character) or change inthe organoleptic perception in response to moisture during the use ofthe product and extend flavor perception and mouthfeel over an extendedperiod of time.

The controlled release system of the present invention is a free-flowingpowder formed of solid hydrophobic nanospheres comprising one or more offlavors, sensory markers, and active ingredients that are encapsulatedin a moisture sensitive microsphere that can also encapsulate the sameor other flavors, sensory markers, and active ingredients, as shown inFIG. 1. The term “spheres” is intended to describe solid, substantiallyspherical particulates. It will be appreciated that other shapes can beformed in accordance with the teachings of the present invention.

The nanospheres of the present invention have an average diameter in therange from about 0.01 micron to about 10 microns. Preferably, the spheresize of the nanospheres is in the range from about 0.05 microns to about2 microns. This linear dimension for any individual sphere representsthe length of the longest straight line joining two points on thesurface of the sphere.

Additional vitamins, biologically or nutritionally active components,edible active ingredients, and pharmaceutical active ingredients can beadded to the controlled release system of the present invention.

Nutraceutical components can include components which promote health orprevent disease or enhance well-being such as antioxidants,phytochemicals, hormones, vitamins such as Vitamins A, B1, B2, B6, B12;C, D, E, K, pantothenate, folic acid, pro-vitamins, minerals such ascalcium, selenium, magnesium salts, available iron, and iron salts,microorganisms such as bacteria, such as live lactobacilli, fungi, andyeast, prebiotics, probiotics, trace elements, essential and/or highlyunsaturated fatty acids such as omega-3 fatty acids, and mid-chaintriglycerides, nutritional supplements, enzymes such as amylases,proteases, lipases, pectinases, cellulases, hemicellulases,pentosanases, xylanases, and phytases, pigments, oligopeptides,dipeptides, and amino acids, and mixtures thereof.

The multi-component release system of the present invention can be usedin food products. The term “food product” refers to material of eitherplant or animal origin or of synthetic sources that contain a bodynutrient such as a carbohydrate, protein, fat vitamin, mineral, etc. Themulti-controlled release system of the present invention can beincorporated into foods intended for human or animal consumption such asbaked goods, for example, bread, wafers, cookies, crackers, pretzels,pizza, and rolls, ready-to-eat breakfast cereals, hot cereals, pastaproducts, snacks such as fruit snacks, salty snacks, grain-based snacks,and microwave popcorn, dairy products such as yogurt, cheese, and icecream, sweet goods such as hard candy, soft candy, and chocolate, animalfeed, pet foods such as dog food and cat food, aqua-culture foods suchas fish food and shrimp feed, and special purpose foods such as babyfood, infant formulas, hospital food, medical food, sports food,performance food or nutritional bars, or fortified foods, foodpre-blends or mixes for home or food service use, such as pre-blends forsoups or gravy, dessert mixes, dinner mixes, baking mixes such as breadmixes, and cake mixes, and baking flour. The discrete particulates ofthe present invention may be used as a topping for breakfast cereals,snacks, soups, salad, cakes, cookies, crackers, puddings, desserts orice cream. They may also be used as a granular ingredient for yogurts,desserts, puddings, custards, ice cream or other pasty or creamy foods.The food products can include for example, baking products such aschocolate, sauces and soups or the like.

If a final product is a baked good the release system of the presentinvention will be mixed with other conventional baking ingredients andthen baked to provide the final product. The multi-component controlledrelease system of the present invention can be used in beverages such aspowdered drink mixes and liquid drinks.

For example, the multi-component controlled release system of thepresent invention can be employed in hydratable sauces and soups. Saucesand soups according to the invention, can be made in a brand variety offlavors and textures. Various flavors can be encapsulated in themulti-component controlled release system of the present inventiondepending upon the desired flavor and texture of the sauce or soup whenthe sauce or soup is hydrated. Flavor ingredients can includecrystalline ingredients such as sugar, salt, citric acid and substitutestherefor; dairy ingredients such as dry milk, cheeses, cream powders andthe like; spices, natural and artificial flavors, and thickening agentssuch as starches (native, modified, waxy, etc.), protein compounds(e.g., albumin, globulin, egg protein or whey protein concentrate) andvegetable gums and any combination thereof.

The multi-component controlled release system can be used in beverages.For example, powder drink mixes can employ the controlled release systemof the present invention.

If a powdered drink mix is desired, the controlled release system of thepresent invention can encapsulate flavorants and be blended withsuspending agents and the like to form a final dry mix product. Toproduce a liquid drink the controlled release system of the presentinvention can encapsulate flavorants and can be mixed with liquid, e.g.water and other ingredients such as suspending agents and the like toproduce the final drink product.

The multi-component controlled release system of the present inventioncan be used in a nutraceutical. The term “nutraceutical” refers to anycompounds or chemicals that can provide dietary or health benefits whenconsumed by humans or animals. Examples of nutraceuticals includevitamins, minerals and others.

The biodegradable multi-component controlled release system provided bythe present invention can generally be incorporated into any suitableconventional oral hygiene product. Exemplary delivery systems includegels, chewing gums, toothpaste, and mouthwash. The toothpaste caninclude other conventional components such as an abrasive such as,silica or alumina, having a particle size of between about 5 microns andabout 50 microns, a thickener such as, colloidal silica having aparticle size of between about 0.1 microns and about 1 micron, and neatflavor oil. The oral hygiene product can be appropriately selecteddepending upon the physical location for delivery of the nano-particlesand the intended use of the nano-particles. The above-describedexemplary delivery systems are preferred in accordance with the presentinvention, since they permit effective delivery of the bioadhesivenano-particles into the oral cavity.

The additional components are usually present in an amount from about 1%to about 20% by weight of the spheres.

I. Matrix Materials for Forming the Nanospheres

Considerations in the selection of the matrix material include goodbarrier properties to the active ingredients, low toxicity andirritancy, stability, integrity, and high loading capacity for theactive agents of interest. Suitable wax materials for the compositionsand devices of the present invention are inert nontoxic materials with amelting point range between about 30° C. and about 90° C. andpenetration point of about 1 to about 10. Examples of wax materialsinclude natural waxes, synthetic waxes and mixtures thereof. Suitablewaxes also include natural, regenerated, or synthetic food approvedwaxes including animal waxes such as beeswax, vegetable waxes such ascarnauba, candelilla, sugar cane, rice bran, and bayberry wax, mineralwaxes such as petroleum waxes including paraffin and microcrystallinewax, and mixtures thereof.

Other wax materials that are known to those skilled in the art andsuitable materials as described in “Industrial Waxes” Vol. I and II, byBennett F.A.I.C., published by Chemical Publishing Company Inc., 1975and Martindale, “The Extra Pharmacopoeia”, The Pharmaceutical Press,28^(th) Edition pp. 1063-1072, 1982 can be used in the presentinvention.

Suitable fat materials and/or glyceride materials which can be used inthe present invention include, but are not limited to, the followingclasses of lipids: mono-, di and triglycerides, phospholipids,sphingolipids, cholesterol and steroid derivatives, terpenes andvitamins. Examples of solid fat materials which can be used in thepresent invention, include solid hydrogenated castor and vegetable oils,hard fats, and mixtures thereof. Other fat materials which can be used,include triglycerides of food grade purity, which can be produced bysynthesis or by isolation from natural sources. Natural sources caninclude animal fat or vegetable oil, such as soy oil, as a source oflong chain triglycerides (LCT). Other triglycerides suitable for use inthe present invention are composed of a majority of medium length fattyacids (C10-C18), denoted medium chain triglycerides (MCT). The fattyacid moieties of such triglycerides can be unsaturated orpolyunsaturated and mixtures of triglycerides having various fatty acidmaterial. Steroids which can be used include as fat materials, but arenot limited to, cholesterol, cholesterol sulfate, cholesterolhemisuccinate, 6-(5-cholesterol 3 beta-yloxy)hexyl6-amino-6-deoxy-1-thio-alpha-D-galactopyranoside, 6-(5-cholesten-3beta-tloxy)hexyl-6-amino-6-deoxyl-1-thio-alpha-D mannopyranoside andcholesteryl)4′-trimethyl 35 ammonio)butanoate.

The fat material can be fatty acids and derivatives thereof which caninclude, but are not limited to, saturated and unsaturated fatty acids,odd and even number fatty acids, cis and trans isomers, and fatty acidderivatives including alcohols, esters, anhydrides, hydroxy fatty acidsand prostaglandins. Saturated and unsaturated fatty acids that can beused include, but are not limited to, molecules that have between 12carbon atoms and 22 carbon atoms in either linear or branched form.Examples of saturated fatty acids that can be used include, but are notlimited to, lauric, myristic, palmitic, and stearic acids. Examples ofunsaturated fatty acids that can be used include, but are not limitedto, lauric, physeteric, myristoleic, palmitoleic, petroselinic, andoleic acids. Examples of branched fatty acids that can be used include,but are not limited to, isolauric, isomyristic, isopalmitic, andisostearic acids and isoprenoids. Fatty acid derivatives include12-(((7′-diethylaminocoumarin-3yl)carbonyl)methylamino)-octadecanoicacid; N-[12-(((7′diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadecanoyl]-2 -aminopalmitic acid, Nsuccinyl-dioleoylphosphatidylethanol amine and palmitoyl-homocysteine;and/or combinations thereof. Mono, di and triglycerides or derivativesthereof that can be used include, but are not limited to, molecules thathave fatty acids or mixtures of fatty acids between 6 and 24 carbonatoms, digalactosyldiglyceride, 1,2-dioleoyl-sn-glycerol;1,2-cdipalmitoyl-sn-3 succinylglycerol; and1,3-dipalmitoyl-2-succinylglycerol.

Surfactants can also be incorporated into the hydrophobic matrixgenerally include all food approved and pharmaceutically-acceptablesurfactants Sodium lauryl sulfate is a water-soluble salt, produced as awhite or cream powder, crystals, or flakes. Also known as dodecyl sodiumsulfate, sodium lauryl sulfate can be a mixture of sodium alkyl sulfatesconsisting chiefly of sodium lauryl sulfate. Sodium lauryl sulfate isalso known as sulfuric acid monododecyl ester sodium salt. Furthermore,sodium lauryl sulfate is readily available from commercial sources suchas Sigma or Aldrich in both solid form and as a solution. The solubilityof sodium lauryl sulfate is about 1 gm per 10 ml/water. The fatty acidsof coconut oil, consisting chiefly of lauric acid, are catalyticallyhydrogenated to form the corresponding alcohols. The alcohols are thenesterified with sulfuric acid (sulfated) and the resulting mixture ofalkyl bisulfates (alkyl sulfuric acids) is converted into sodium saltsby reacting with alkali under controlled conditions of pH.

Alternative anionic surfactants for use as surface active agents in thepresent invention include docusate salts such as the sodium saltthereof. Other suitable anionic surfactants include, without limitation,alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acylsarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fattyacid, polypeptide condensates and sulfuric acid esters.

In other aspects of the invention amphoteric (amphipathic/amphiphilicsurfactants), non-ionic surfactants and/or cationic surfactants can beused as the surface active agent in the coprocessed compositions of thepresent invention. Suitable pharmaceutically-acceptable non-ionicsurfactants include, for example, polyoxyethylene compounds, lecithin,ethoxylated alcohols, ethoxylated esters, ethoxylated amides,polyoxypropylene compounds, propoxylated alcohols,ethoxylated/propoxylated block polymers, propoxylated esters,alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,ethylene glycol esters, diethylene glycol esters, propylene glycolesters, glycerol esters, polyglycerol fatty acid esters, SPAN's (e.g.,sorbitan esters), TWEEN's (i.e., sucrose esters), glucose (dextrose)esters and simethicone.

Other suitable pharmaceutically-acceptable surfactants include acacia,benzalkonium chloride, cholesterol, emulsifying wax, glycerolmonostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene,and castor oil derivatives.

The nanospheres of the present invention can have a melting point in therange from about 30° C. to about 90° C., preferably from about 40° C. toabout 90° C. The melting point of the spheres is usually a function ofthe carrier matrix employed. Accordingly, preferred matrix materialshave a melting point in the range of about 50° C. to about 80° C.,preferably from about 60° C. to about 70° C. It should be understoodthat it is the melting point of the sphere rather than of the carriermatrix that is important for use of the carrier system of the presentinvention.

II. Matrix Materials for Forming the Microspheres

Moisture-Sensitive and Bioadhesive Materials

Moisture-sensitive materials for forming the microspheres of the presentinvention comprise water soluble and water dispersible syntheticpolymers and copolymers, starch derivatives, polysaccharides,hydrocolloids, natural gums, proteins, and mixtures thereof.

Examples of synthetic water sensitive polymers which are useful for theinvention include polyvinyl pyrrolidone, water soluble celluloses,polyvinyl alcohol, ethylene maleic anhydride copolymer, methylvinylether maleic anhydride copolymer, acrylic acid copolymers, anionicpolymers of methacrylic acid and methacrylate, cationic polymers withdimethyl-aminoethyl ammonium functional groups, polyethylene oxides,water soluble polyamide or polyester.

Examples of water soluble hydroxyalkyl and carboxyalkyl cellulosesinclude hydroxyethyl and carboxymethyl cellulose, hydroxyethyl andcarboxyethyl cellulose, hydroxymethyl and carboxymethyl cellulose,hydroxypropyl carboxymethyl cellulose, hydroxypropyl methyl carboxyethylcellulose, hydroxypropyl carboxypropyl cellulose, hydroxybutylcarboxymethyl cellulose, and the like. Also useful are alkali metalsalts of these carboxyalkyl celluloses, particularly and preferably thesodium and potassium derivatives.

Polyvinyl alcohol useful in the practice of the invention is partiallyand fully hydrolyzed polyvinyl acetate, termed “polyvinyl alcohol” withpolyvinyl acetate as hydrolyzed to an extent, also termed degree ofhydrolysis, of from about 75% up to about 99%. Such materials areprepared by means of any of Examples I-XIV of U.S. Pat. No. 5,051,222issued on Sep. 24, 1991, the specification for which is incorporated byreference herein.

A polyvinyl alcohol useful for practice of the present invention isMowiol® 3-83, having a molecular weight of about 14,000 Da and degree ofhydrolysis of about 83%, Mowiol® 3-98 and a fully hydrolyzed (98%)polyvinyl alcohol having a molecular weight of 16,000 Da commerciallyavailable from Gehring-Montgomery, Inc. of Warminister Pa. Othersuitable polyvinyl alcohols are: AIRVOL® 205, having a molecular weightof about 15,000-27,000 Da and degree of hydrolysis of about 88%, andVINEX® 1025, having molecular weight of 15,000-27,000 Da degree ofhydrolysis of about 99% and commercially available from Air Products &Chemicals, Inc. of Allentown, Pa.; ELVANOL® 51-05, having a molecularweight of about 22,000-26,000 Da and degree of hydrolysis of about 89%and commercially available from the Du Pont Company, Polymer ProductsDepartment, Wilmington, Del.; ALCOTEX® 78 having a degree of hydrolysisof about 76% to about 79%, ALCOTEX® F88/4 having a degree of hydrolysisof about 86% to about 88% and commercially available from the HarlowChemical Co. Ltd. of Templefields, Harlow, Essex, England CM20 2BH; andGOHSENOL® GL-03 and GOHSENOL® KA-20 commercially available from NipponGohsei K.K., The Nippon Synthetic Chemical Industry Co., Ltd., of No.9-6, Nozaki Cho, Kita-Ku, Osaka, 530 Japan.

Suitable polysaccharides are polysaccharides of the non-sweet,coloidally-soluble types, such as natural gums, for example, gum arabic,starch derivates, dextrinized and hydrolyzed starches, and the like. Asuitable polysaccharide is a water dispersible, modified starchcommercially available as Capule®, N-Lok®, Hi-Cap™ 100 or Hi-Cap™ 200commercially available from the National Starch and Chemical Company ofBridgewater, N.J.; Pure-Cote™, commercially available from the GrainProcessing Corporation of Muscatine, Iowa. In the preferred embodimentthe natural gum is a gum arabic, commercially available from TIC GumsInc. Belcamp, Midland. Suitable hydrocolloids are xanthan, maltodextrin,galactomanan or tragacanth, preferably maltodextrins such as Maltrin™M100, and Maltrin™ M150, commercially available from the GrainProcessing Corporation of Muscatine, Iowa.

Enhancing the deposition of the nanospheres onto either the epithelialsurface or the mucus can increase their residence time in the oralcavity and increase pharmaceutical and medical aspects of bioadhesivesystems for drug delivery. Incorporating bioadhesive polymers in thenanosphere or the microsphere matrix can be utilized to control orincrease the absorption of the nanosphere through the mucosal lining, orto further delay transit of the nanosphere through the gastrointestinalpassages.

A bioadhesive polymer as used in the disclosure is one that binds tomucosal epithelium under normal physiological conditions. Bioadhesion inthe gastrointestinal tract proceeds in two stages: (1) viscoelasticdeformation at the point of contact of the synthetic material into themucus substrate, and (2) formation of bonds between the adhesivesynthetic material and the mucus or the epithelial cells. In general,adhesion of polymers to tissues can be achieved by (i) physical ormechanical bonds, (ii) primary or covalent chemical bonds, and/or (iii)secondary chemical bonds such as ionic. Physical or mechanical bonds canresult from deposition and inclusion of the bioadhesive material in thecrevices of the mucus or the folds of the mucosa. Secondary chemicalbonds, contributing to bioadhesive properties, can comprise dispersiveinteractions such as Van der Waals interactions and stronger specificinteractions, such as hydrogen bonds. Hydrophilic functional groupsprimarily responsible for forming hydrogen bonds include hydroxyl andthe carboxylic groups. Suitable bioadhesive polymers for use in thepresent invention include bioerodible hydrogels as described by H. S.Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules. 1993,26:581-587, the teachings of which are incorporated herein,polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides,polyacrylic acid, alginate, chitosan, poly(methyl methacrylates),poly(ethyl methacrylates), poly (butyl methacrylate), poly(isobutylmethacrylate), poly(hexl methacrylate), poly(isodecl methacrylate),poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methylacrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), andpoly(octadecl acrylate) and poly(fumaric-co-sebacic)acid.

Polymers with enhanced bioadhesive properties can be provided whereinanhydride monomers or oligomers are incorporated into the polymer. Theoligomer excipients can be blended or incorporated into a wide range ofhydrophilic and hydrophobic polymers including proteins, polysaccharidesand synthetic biocompatible polymers. Anhydride oligomers can becombined with metal oxide particles to improve bioadhesion in additionto the use of organic additives alone. Organic dyes because of theirelectronic charge and hydrophobicity/hydrophilicity can either increaseor decrease the bioadhesive properties of polymers when incorporatedinto the polymers. The incorporation of oligomer compounds into a widerange of different polymers which are not normally bioadhesive can beused to increase the adherence of the polymer to tissue surfaces such asmucosal membranes.

III. Flavors, Sensory Markers and Other Active Ingredients

Various flavors and active ingredients can be incorporated in thehydrophobic nanosphere matrix, in the water sensitive microspherematrix, or in both the nano and micro spheres matrices. The activeingredients, flavors, and sensory markers encapsulated in thenanospheres can be the same or different than those encapsulated in themicrospheres. Flavors can be included in the controlled system of thepresent invention. The flavors that can be encapsulated in the system ofthe present invention can be any flavor material and can be selectedaccording to the desires of the flavor creator. In general terms, suchflavor materials are characterized by a vapor pressure below atmosphericpressure at ambient temperatures. The high boiling flavor materialsemployed herein will most often be solids at ambient temperatures, butalso can include high boiling liquids. A wide variety of chemicals areknown for flavor uses, including materials such as aldehydes, ketones,esters, and the like. More commonly, naturally occurring plant andanimal oils and exudates comprising complex mixtures of various chemicalcomponents are known for use as flavors and such materials can be usedherein. Flavors useful for the present invention can be a single aromachemical, relatively simple in their composition, or can comprise highlysophisticated, complex mixtures of natural and synthetic chemicalcomponents, all chosen to provide any desired flavor.

Flavor materials suitable for use in the present invention are describedmore fully in S. Arctander, Perfume Flavors and Chemicals, Vols. I andII, Aurthor, Montclair, N.J. and the Merck Index, 8th Edition, Merck &Co., Inc. Rahway, N.J., both references being incorporated herein byreference.

Suitable cooling agents which can be included in the controlled releasesystem of the present invention include menthol, non-volatile mentholanalogs such as menthyl lactate, menthyl ethoxyacetate, menthoneglycerinacetal, 3-1-menthoxypropane-1,2-diol, ethyl 1-menthyl carbonate,(1S,3S,4R)-p-menth-8-en-3-ol, menthyl pyrrolidone carboxylate,N-substituted-p-menthane-3-carboxamides (as described in U.S. Pat. No.4,136,163, which is incorporated herein by reference) including, forexample, N-ethyl-p-menthane-3-carboxamide, (such acyclic carboxamidesbeing described in U.S. Pat. No. 4,153,679, which is incorporated hereinby reference) including, for example,N,2,3-trimethyl-2-isopropylbutanamide, and ketal coolants (as describedin WO 93/23005, which is incorporated herein by reference) including,for example, 1-menthon-1d-isomenthon glycerin ketal. Suitable coolingagents which can be used are 3-1-menthoxypropane-1,2-diol,N-ethyl-p-menthane-3-carboxamide (WS-3),N,2,3-trimethyl-2-isopropylbutanamide (WS-23), menthyl lactate(Frescolat ML), menthone glycerinacetal (Frescolat MGA) and menthylethoxyacetate (Menglytate).

Additional vitamins, biologically or nutritionally active components,edible active ingredients, and pharmaceutical active ingredients can beadded to the controlled release system of the present invention.

Nutraceutical components may include components which promote health orprevent disease or enhance well-being such as antioxidants,phytochemicals, hormones, vitamins such as Vitamins A, B1, B2, B6, B12;C, D, E, K, pantothenate, folic acid, pro-vitamins, minerals such ascalcium, selenium, magnesium salts, available iron, and iron salts,microorganisms such as bacteria, such as live lactobacilli, fungi, andyeast, prebiotics, probiotics, trace elements, essential and/or highlyunsaturated fatty acids such as omega-3 fatty acids, and mid-chaintriglycerides, nutritional supplements, enzymes such as amylases,proteases, lipases, pectinases, cellulases, hemicellulases,pentosanases, xylanases, and phytases, pigments, oligopeptides,dipeptides, and amino acids, and mixtures thereof.

IV. Processing Method

IVa. Nanospheres

The encapsulated flavors, and active ingredients in the nanospheres ofthe present invention can be prepared by the steps of (1) heatinghydrophobic materials to a temperature above the melting point to form amelt, (2) dissolving or dispersing the first said flavor, and first saidactive ingredients in the melt, (4) emulsifying the melt in the aqueousphase; and (5) cooling the dispersion to ambient temper to form a finesuspension.

The flavors, other active ingredients can be incorporated into thehydrophobic solid nanospheres. Preferably, about 1% to about 80% of andmore preferably about 1% to about 60% by weight of the activeingredients are used in forming the nanospheres.

IVb. Microspheres

The controlled release system of the present invention can be preparedby the steps of (a) incorporating the selected flavors, and activeingredients into the hydrophobic interior of the nanospheres, (b)forming an aqueous mixture comprising one or more flavor, and activeagents, the nanospheres, and a water sensitive material, and (c) spraydrying the mixture of the present invention to form a dry powdercomposition. Accordingly, the nanospheres can be encapsulated into themicrosphere structure. One or more of the flavors, or activeingredients, which can be the same or different than the, flavors, andactive ingredients incorporated in the nanosphere can be incorporatedinto the microsphere structure.

A process for producing the multi component controlled release systemcan include the following steps:

-   -   (i) heating hydrophobic materials to a temperature above the        melting point of the materials to form a melt;    -   (ii) dissolving or dispersing the first said flavor into the        melt;    -   (iii) dissolving or dispersing the first said active ingredients        into the melt;    -   (iv) dissolving or dispersing a second said flavor, second said        active ingredients, and moisture sensitive and or bioadhesive        materials, such as, starch derivatives, natural gums, polyvinyl        alcohol, proteins, hydrocolloids, or mixture of thereof, in the        aqueous phase;    -   (v) heating the composition to above the melting temperature of        the hydrophobic materials;    -   (vi) mixing the hot melt with the aqueous phase to form a        dispersion;    -   (vii) high shear homogenization of the dispersion at a        temperature above the melting temperature until a homogeneous        fine dispersion is obtained having a sphere size of from about 1        micron to about 2 microns;    -   (viii) cooling the dispersion to ambient temperature; and    -   (ix) spray drying the emulsified mixed suspension to form a dry        powder composition.

Homogenization can be accomplished in any suitable fashion with avariety of mixers known in the art such as simple paddle or ribbonmixers although other mixers, such as ribbon or plow blenders, drumagglomerators, and high shear mixers may be used. Suitable equipment forthis process include a model Rannie 100 lab homogenizer available fromAPV Gaulin Inc. Everett, Mass., a rotor stator high shear mixeravailable from Silverson Machines, of East Long Meadow, Mass., or ScottProcessing Equipment Corp. of Sparta, N.J., and other high sear mixers.

The suspension is spray dried to remove the excess water. Spray dryingis well known in the art and been used commercially in manyapplications, including foods where the core material is a flavoring oiland cosmetics where the core material is a fragrance oil. Cf. Balassa,“Microencapsulation in the Food Industry”, CRC Critical Review Journalin Food Technology, July 1971, pp 245-265; Barreto, “Spray DriedPerfumes for Specialties, Soap and Chemical Specialties”, December 1966;Maleeny, Spray Dried Perfumes, Soap and San Chem, January 1958, pp. 135et seq.; Flinn and Nack, “Advances in Microencapsulation Techniques”,Batelle Technical Review, Vo. 16, No. 2, pp. 2-8 (1967); U.S. Pat. Nos.5,525,367 and 5,417,153 which are incorporated herein as references.

In the preferred embodiment, the active agent is present at a level fromabout 0.01% to about 60%, preferably from about 1% to about 50% byweight of the microsphere. In the preferred embodiment, the nanospheresare generally present in the water sensitive matrix at a level fromabout 1% to about 80%, preferably from about 1% to about 60% by weightof the matrix material with the balance being the fragrances, flavors,other active ingredients, and the water sensitive materials. In thepreferred embodiment, the moisture sensitive matrix is generally presentat a level from about 1% to about 80%, preferably from about 1% to about60% by weight of the matrix material with the balance being thefragrances, flavors, other active ingredients, and the hydrophobicmaterials.

In one embodiment microspheres are formed by mixing nanospheresincorporating a selected active agent with polyvinyl alcohol, orcompositions of polyvinyl alcohol and polysaccharides, under conditionssufficient to encapsulate the nanospheres. Preferably mixing a selectedactive agent with the polyvinyl alcohol, or compositions of polyvinylalcohol and polysaccharides, until the emulsion is formed and then spraydrying the emulsion to thereby form an encapsulated nanosphere. In thepreferred embodiment, the moisture sensitive matrix is formed of apolyvinyl alcohol material at a level from about 1% to about 80%,preferably from about 1% to about 70% by weight of the matrix materialwith the balance being the amount by weight of active agents and anoptimal amount of polysaccharides. In an alternate embodiment, polyvinylalcohol is present in the matrix material in an amount of about 1% toabout 80% and the weight of the polysaccharides are present in theamount of about 1% to about 80%. In the preferred embodiment, the activeagent composition is generally present at a level from about 0.01% toabout 80% preferably from about 1% to about 50% by weight of theencapsulated active agent with the balance being the polyvinyl alcoholor polyvinyl alcohol and polysaccharides. Optionally other conventionalingredients known in the art such as preservatives, surfactants, can beused in accordance with the teachings of the present invention. Themulti-component spheres of the present invention preferably have size offrom about 0.5 micron to about 300 microns, more preferably from about 1micron to about 200 microns, most preferably from about 2 microns toabout 50 microns. The present invention preferably has minimal activeagents on the surface of the spheres, preferably less than 1%.

Polyvinyl alcohol is an excellent barrier material to the permeation ofthe volatile fragrance ingredients, and as a result the controlledrelease systems of the present invention do not provide perceptible odorin the dry state. Upon wetting by a sufficient amount of aqueous fluidsuch as a perspiration, or wetting the lips, the matrix can eitherdissolve to provide a burst of the active ingredients, or swell andsoften the matrix to slowly release the encapsulated active agents overan extended period of time, depending on the composition of the matrix,such as the ratio of polyvinyl alcohol to other matrix materials. Theuse of moisture activated spheres which provide varying rates ofdiffusion are contemplated. For example, the moisture activated spheresmay diffuse at any of the rates of the following:

-   -   (i) at steady-state or zero-order release rate in which there is        a substantially continuous release per unit of time;    -   (ii) a first-order release rate in which the rate of release        declines towards zero with time; and    -   (iii) a delayed release in which the initial rate is slow, but        then increases with time.

It has been found that a greater amount of polyvinyl alcohol in thematrix provides slower release rate as compared to a matrix including alesser amount of polyvinyl alcohol in combination with a polysaccharide.For example, a matrix having about 70% to about 80% polyvinyl alcoholhas a slower release rate than a matrix having about 30% to about 40%polysaccharide and about 40% to about 50% polyvinyl alcohol. Forexample, if a high amount of polyvinyl alcohol is used in the matrix,such as in the range of about 70% to about 80%, the matrix providescontrolled release of the active agent over an extended period of timefrom the time the matrix contacts moisture up to forty-eight hours. Ifpolyvinyl alcohol is combined with polysaccharide in the matrix, such asin the amount of 30% to about 40% polyvinyl alcohol and 30% to about 40%of polysaccharide, a greater amount of active agent is released uponcontract with moisture to provide a “burst” of the active agent and theactive agent is released over a shorter period of time for example fromthe time the matrix contacts the fluid up to the range of about 6 hoursto about twenty-four hours. Typically, the active agent at the surfaceof the sphere can be released upon contact with the fluid with theremainder of the active agent being either released in a burst if thematrix dissolves or over an extended period of time upon swelling andsoftening of the matrix.

Nanospheres formed of a hydrophobic material provide a controlledrelease system in order to release the active agent over an extendedperiod of time by molecular diffusion. Fragrances, flavors, and otheractive agents in the hydrophobic matrix of the nanospheres can bereleased by transient diffusion. The theoretical early and late timeapproximation of the release rate of the active ingredients dissolved inthe hydrophobic matrix of the nanospheres can be calculated from thefollowing equations:Early Time Approximation $\begin{matrix}{{{\left( {m_{t}/m_{\sec}} \right) < 0.4}\quad{\frac{M_{t}}{M_{\infty}} = {{4\left( \frac{D_{p}t}{\Pi\quad r^{2}} \right)^{1/2}} - \frac{D_{p}t}{r^{2}}}}}\quad} & (1) \\{\frac{{\mathbb{d}M_{t}}/M_{\infty}}{\mathbb{d}t} = {{2\left( \frac{D_{p}}{\Pi\quad r^{2}t} \right)^{1/2}} - \frac{D_{p}}{r^{2}}}} & (2)\end{matrix}$Late Time Approximation $\begin{matrix}{{{\left( {m_{t}/m_{\infty}} \right) > 0.6}\quad{\frac{M_{t}}{M_{\infty}} = {1 - {\frac{4}{(2.405)^{2}}{\exp\left( \frac{{- (2.405)^{2}}D_{p}t}{r^{2}} \right)}}}}}\quad} & (3) \\{\frac{{\mathbb{d}M_{t}}/M_{\infty}}{\mathbb{d}t} = {1 - {\frac{4D_{p}}{r^{2}}{\exp\left( \frac{{- (2.405)^{2}}D_{p}t}{r^{2}} \right)}}}} & (4)\end{matrix}$

-   -   wherein:    -   r is the radius of the cylinder,    -   m∞ is the amount fragrance released from the controlled release        system after infinite time;    -   m_(t) is the amount fragrance released from the controlled        release system after time t; and    -   D_(p) is the diffusion coefficient of the fragrance or aroma        chemical in the matrix.        The release rate for releasing the flavor, or other active        agents from the hydrophobic nanospheres is typically slower than        the release rate for releasing active agent from the moisture        sensitive matrix. The active agents can be incorporated into        either the hydrophobic nanospheres or the moisture sensitive        matrix depending on the desired time for release of the active        agents. For example, a predetermined first active agent can be        incorporated in the moisture sensitive matrix to be released        upon product consumption and a predetermined second active agent        can be incorporated in the hydrophobic nanospheres for release        over an extended period of time during or after the first agent        has been released. For example, the moisture sensitive matrix        formed in accordance with the present invention can release the        first active agent upon contact with moisture to provide a        “burst” with continued release of the first active agent and        nanospheres formed in accordance with the present invention can        release the active agent depending on the release rate from an        initial time such as within few hours, up to a period of few        days.        V. Bioadhesion Measurements

The oral cavity is lined by non-keratinized, stratified, squamousepithelial cells. These types of epithelial cells also lines other softtissue surfaces that include esophagus, vagina and cervix. A HeLa cellline that has been used to determine the ability of the nanospheres toadhere and reside in the oral cavity is an epithelial-like cell line,originally derived from a carcinoma of the cervix. HeLa cells arecultured in Minimal Essential Medium (Eagles) with 10% fetal bovineserum. To test the adherence of nanospheres to the cell surface, HeLacells are being plated at a density of 2×10⁵ cells per dish (35 mm) in 2ml medium. Three dishes are seeded for each data point. On the followingday, the nanospheres are being dispersed in 1 ml medium. The medium inwhich the cells are cultured is aspirated and replaced immediately withthe nanospheres-containing medium. The nanospheres are left to adhere tothe cells by gravity for time periods such as 5 minutes, 15 minutes, and30 minutes. At each time point the medium is aspirated, and the cellssurface are gently rinsed twice with 2 ml medium, simulating rise of themouth by saliva or rinsing the mouth with water following brush. Cellsare imaged immediately using an Olympus IX-70 inverted fluorescentmicroscope and Princeton Instruments Micromax cooled CCD camera. Theimages are saved and stored and analyzed using the IPLab ScientificImaging Software (Scanalytics, Inc, VA) to determine the number ofparticles adherent to the cells per field. Images from three randomfields are collected from each dish. Each experiment generates a totalof nine data points, for each time point. The nine data points areaveraged. Each experiment is repeated at least 3 times. Results obtainedfrom three or more independent experiments are averaged and expressed asa mean±standard deviation (SD). The data are subjected to statisticalanalysis using the StatView program using Student's t-test method todetermine whether the difference among groups is statisticallysignificant. Results are accepted as significant when p<0.05. Theability of the nanospheres of the present invention to adhere to HeLacultured cells is shown in FIG. 2. FIG. 3 shows specific adhesion ofnanospheres described in examples 1 to 4 to HeLa cells.

The invention can be further illustrated by the following examplesthereof, although it will be understood that these examples are includedmerely for purposes of illustration and are not intended to limit thescope of the invention unless otherwise specifically indicated. Allpercentages, ratios, and parts herein, in the Specification, Examples,and Claims, are by weight and are approximations unless otherwisestated.

Preparation of Dual Flavor Controlled Release System

EXAMPLE 1

The following procedure is used for the preparation of a controlledrelease system that provides flavor transition as well as deliversvitamin E for extended period of time. A peppermint flavor and vitamin Eare encapsulated in the hydrophobic nanospheres and a fruity flavor isencapsulated in the water sensitive microsphere. The nanosphereshydrophobic matrix is candelilla wax, commercially available from Strahl& Pitsch Inc. of West Babylon, N.Y. The microsphere water sensitivematrix is Hi-Cap™ 100 (commercially available from the National Starchand Chemical Company of Bridgewater, N.J.).

100 grams of candelilla wax is placed in an oven at 80° C. and allowedto melt. 1500 grams of deionized water are placed into 1 gallon vessel,fitted with an all-purpose silicon rubber heater (Cole-Palmer InstrumentCompany). 500 grams of Hi-Cap™ 100 (commercially available from theNational Starch and Chemical Company of Bridgewater, N.J.) was added tothe water and the aqueous solution is heated to 90° C. while mixing itwith a propeller mixer. The candelilla wax is removed from the oven and50 grams of peppermint flavor (commercially available from Noville Inc.of South-Hackensack, N.J.) and 50 grams of vitamin E (commerciallyavailable from JEEN International Corporation of Little Fall, N.J.) aremixed into the melt by hand with a glass rod. The flavor/vitamin E/waxmixture is poured into the aqueous solution and the dispersion and 300grams of a fruity flavor (commercially available from Noville Inc. ofSouth-Hackensack, N.J.) are homogenized at 20,000 psi using a Rannie 100lab homogenizer available from APV Gaulin Inc. The dispersion is cooledto ambient temperature by passing it through a tube-in-tube heatexchanger (Model 00413, Exergy Inc. Hanson Mass.) to form a suspension.The resulting suspension is spray dried with a Bowen Lab Model Drier (atSpray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with an inlettemperature of 380° F., and outlet temperature of 225° F. and a wheelspeed of 45,000 r.p.m to produce a free flowing, dry powder, consistingof 5% peppermint flavor and 5% vitamin E encapsulated in the solidhydrophobic nanospheres. The controlled release system obtained contains5% peppermint flavor, 5% vitamin E, 10% candelilla wax, 30% fruityflavor, and 50% water sensitive material.

EXAMPLE 2

The following procedure is used for the preparation of a controlledrelease system that provides flavor transition as well as releases acooling agent for extended period of time. A cooling agent (WS-3commercially available from Millennium Specialty Chemicals, ofJacksonville, Fla.) is encapsulated in the hydrophobic nanospheres and afruity flavor (commercially available from Noville Inc. ofSouth-Hackensack, N.J.) is encapsulated in the water sensitivemicrosphere. The nanospheres hydrophobic matrix is candelilla wax,commercially available from Strahl & Pitsch Inc. of West Babylon, N.Y.The microsphere water sensitive matrix is Hi-Cap™ 100 (commerciallyavailable from the National Starch and Chemical Company of Bridgewater,N.J.).

150 grams of candelilla wax is placed in an oven at 80° C. and allowedto melt. 1500 grams of deionized water are placed into 1 gallon vessel,fitted with an all-purpose silicon rubber heater (Cole-Palmer InstrumentCompany). 450 grams of Hi-Cap™ 100 (commercially available from theNational Starch and Chemical Company of Bridgewater, N.J.) was added tothe water and the aqueous solution is heated to 90 degree C. whilemixing it with a propeller mixer. The candelilla wax is removed from theoven and 100 grams of cooling agent (WS-3 commercially available fromMillennium Specialty Chemicals, of Jacksonville, Fla.) is mixed into themelt by hand with a glass rod. The cooling agent/wax mixture is pouredinto the aqueous solution and the dispersion and 300 grams of a fruityflavor (commercially available from Noville Inc. of South-Hackensack,N.J.) are homogenized at 20,000 psi using a Rannie 100 lab homogenizeravailable from APV Gaulin Inc. The dispersion is cooled to ambienttemperature by passing it through a tube-in-tube heat exchanger (Model00413, Exergy Inc. Hanson Mass.) to form a suspension. The resultingsuspension is spray dried with a Bowen Lab Model Drier (at Spray-Tek ofMiddlesex, N.J.) utilizing 250 c.f.m of air with an inlet temperature of380° F., and outlet temperature of 225° F. and a wheel speed of 45,000r.p.m to produce a free flowing, dry powder, consisting of 10% Coolingagent encapsulated in the solid hydrophobic nanospheres. The controlledrelease system obtained contains 10% cooling agent, 15% candelilla wax,30% fruity flavor, and 45% water sensitive material.

EXAMPLE 3

The following procedure is used for the preparation of a controlledrelease system that protect citral against oxidation and provides longlasting citrus mouth feel for extended period of time, by encapsulatingcitral in the hydrophobic nanospheres. The nanospheres hydrophobicmatrix is camauba wax, commercially available from Strahl & Pitsch Inc.of West Babylon, N.Y. The microsphere water sensitive matrix is Hi-Cap™100 (commercially available from the National Starch and ChemicalCompany of Bridgewater, N.J.).

250 grams of camauba wax (commercially available from Strahl & PitschInc. of West Babylon, N.Y.) and 50 grams of polysorbate 80 (commerciallyavailable under the trade name T-MAZ® 80K from BASF of Mt. Olive, N.J.)are placed in an oven at 90° C. and allowed to melt. 1800 grams ofdeionized water are placed into 1 gallon vessel, fitted with anall-purpose silicon rubber heater (Cole-Palmer Instrument Company). 500grams of Hi-Cap™ 100 (commercially available from the National Starchand Chemical Company of Bridgewater, N.J.) was added to the water andthe aqueous solution is heated to 90 degree C. while mixing it with apropeller mixer. The melt is removed from the oven and 200 grams ofcitral (commercially available from Noville Inc. of South-Hackensack,N.J.) are mixed into the melt by hand with a glass rod. Theciral/carnauba/polysorbate 80 mixture is poured into the aqueoussolution and the dispersion and homogenized at 20,000 psi using a Rannie100 lab homogenizer available from APV Gaulin Inc. The dispersion iscooled to ambient temperature by passing it through a tube-in-tube heatexchanger (Model 00413, Exergy Inc. Hanson Mass.) to form a suspension.The resulting suspension is spray dried with a Bowen Lab Model Drier (atSpray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with an inlettemperature of 380° F., and outlet temperature of 225° F. and a wheelspeed of 45,000 r.p.m to produce a free flowing, dry powder, consistingof 20% citral encapsulated in the solid hydrophobic nanospheres. Thecontrolled release system obtained contains 20% citral.

EXAMPLE 4

The following procedure is used for the preparation of a multi componentcontrolled release system comprising menthol as sensory marker andcetylpyridinium chloride (CPC) as both the biologically activeingredient and bioadhesive/mucoadhesive surfactant. The solidhydrophobic nano particles are composed of candelilla wax from Strahl &Pitsch Inc. of West Babylon, N.Y.

300 grams of candelilla wax are placed in an oven at 80° C. and allowedto melt. 1600 grams of deionized water are placed into 1 Gallon vessel,fitted with an all-purpose silicon rubber heater (Cole-Palmer InstrumentCompany). 495 grams of Capsul Starch (commercially available from theNational Starch and Chemical Company of Bridgewater, N.J.) and 5 gramsof CPC are added to the water and the aqueous solution is heated to 90°C. while mixing it with a propeller mixer. The candelilla wax melt isremoved from the oven and 200 grams of menthol are mixed into the wax byhand with a glass rod. The menthol/wax mixture is poured into theaqueous solution and the dispersion is homogenized at 20,000 psi using aRannie 100 lab homogenizer available from APV Gaulin Inc. The dispersionis cooled to ambient temperature by passing it through a tube-in-tubeheat exchanger (Model 00413, Exergy Inc. Hanson Mass.) to form asuspension. The resulting suspension is spray dried with a Bowen LabModel Drier (at Spray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of airwith an inlet temperature of 380° F., and outlet temperature of 225° F.and a wheel speed of 45,000 r.p.m to produce a free flowing, dry powder,consisting of 20% menthol encapsulated in the solid hydrophobic nanoparticles and 0.05% CPC in the water sensitive matrix of the microparticles.

The shape and size of the nano-particles was verified by examining thesamples under a scanning electron microscope (SEM). SEM studies showedthat the nano-particles of Example I were spherical in nature with anaverage particle size of approximately 1 micron. The nanospheres weresubjected to in vitro bioadhesion measurements, utilizing the techniquepreviously described. Measurements of the adhesion of particles to cellswere carried out on the nanospheres, along with the appropriatecontrols, using cultured human epithelial HeLa cells as a model systemas described previously. The nanospheres were observed to exhibitexcellent bioadhesive properties the cultured cells HeLa cells.

The nanospheres of Examples 1-4, exhibit excellent bioadhesiveproperties and the ability to sustain the release of the sensory markerand other active ingredients over extended period of time, when used inbeverages, food products, as well as oral hygiene preparation (inaccordance with the use of U.S. Pat. No. 5,882,630, issued on Mar. 16,1999, entitled “Dentifrices Composition”, incorporated by referenceherein).

EXAMPLE 5

Use of Toothpaste

10 grams of the suspension of Examples I to III is admixed with 90 gramsof a toothpaste composition, as described in U.S. Pat. No. 5,882,630,issued on Mar. 16, 1999, entitled “Dentifrices Composition”,incorporated by reference herein and containing: INGREDIENT % w/wCARBOPOL 974P 1.00 THICKENING SILICA 6.50 ABRASIVE SILICA 14.00 SODIUMFLUORIDE 0.23 TITANIUM DIOXIDE 1.00 ADINOL CT 95 2.00 SACCHARIN 0.33POLYETHYLENE 17.50 GLYCOL(400) GLYCERIN qs

A toothpaste comprising 1% of the neat menthol and another samplecomprising the multi component delivery system of the present inventiondescribed in Example 4 are applied to the teeth by brushing the teethwith 1 gram of the toothpaste followed by rinsing the teeth with 50 ml.of water two times.

Flavor perception in the mouth following the application of the productconsisting of the nanospheres vs. the same product consisting of anequivalent amount of neat flavor, was evaluated organoleptically. Apanel test is conducted to determine which product provides thestrongest perception of flavor (using a scale of 0-10), after 10minutes, 1 hour, and 3 hours following application of the product FlavorIntensity (a scale of 1-10) 10 minutes 1 Hour 3 Hours Toothpaste withneat menthol 3 1 1 Toothpaste with menthol of Example 4 7 5 3The toothpaste containing the multi component controlled release systemif the present invention provided a higher perception of menthol for anextended period of time, compared to the sample containing the neatmenthol. It was readily apparent that the toothpaste containing theinventive multi component system has superior characteristics andprovided longer lasting menthol perception.Incorporation of the Controlled Release System in Chocolate Products

EXAMPLE 6

The controlled release system described in Example 3 was incorporated ina commercial Nestle® baking chocolate. The same level of neat citral oilwas also incorporated in a commercial Nestle® baking chocolate. Theability of the delivery system of the present invention to protectcitral from oxidation and sustain its release was determined by weightloss measurements at 30 degrees C., as are shown in FIG. 4.

The results clearly show that during the first 100 hours we lost about20% of the citral from the chocolate comprising the neat oil, whereas nocitral was lost from the chocolate comprising the encapsulated citral inthe controlled release system of the present invention.

EXAMPLE 7

The controlled release system described in Examples 1 and 2 wereincorporated in a commercial Nestle® baking chocolate. The ability ofchocolate comprising controlled release system of Example 1 and 2 toyield a high impact flavor “burst” upon eating the chocolate, provideflavor transition, and prolong flavor perception in the mouth over anextended period of time was evaluated.

The chocolate bars were tested and flavor character as well as flavorintensity is evaluated. Flavor transition was clearly noticed a minuteafter testing the chocolate. The cooling sensation of the chocolatecomprising the delivery system of example 2 was sensed for 3 hours afterconsumption of the product.

Incorporation of the Controlled Release System in Powder Drink

EXAMPLE 8

The performance of a powder drink comprising the controlled releasesystem of Example 3 (i.e., the ability to yield long lasting citrusmouth feel over extended period of time) was evaluated and compared tothe performance of the same product comprising the neat citral, at thesame level.

Flavor perception in the mouth following the use of the above drinkscomprising the nanospheres vs. the same drink comprising an equivalentamount of neat flavor, was evaluated organoleptically. A panel test isconducted to determine which product provides the strongest perceptionof flavor (using a scale of 0-10), after 1 minutes, 10 minutes, and 20minutes following consumption of the product. Flavor Intensity (a scaleof 1-10) 1 minute 10 minutes 30 minutes Drink with neat citral 4 2 1Drink with citral of Example 3 8 6 4

It is to be understood that the above-described embodiments areillustrative of only a few of the many possible specific embodimentswhich can represent applications of the principles of the invention.Numerous and varied other arrangements can be readily devised inaccordance with these principles by those skilled in the art withoutdeparting from the spirit and scope of the invention.

1. A multi-component moisture activated controlled release deliverysystem for delivery to biological surfaces comprising an oral cavity ormucous membranes of various tissues, said system comprising: a pluralityof solid nano-particles formed of a hydrophobic material, saidhydrophobic material comprises natural wax, synthetic wax, fat,glyceride, fatty acid, fatty acid derivative and mixtures thereof eachof said solid nano-particles comprising a core and an effective amountof a first active agent contained therein, said plurality ofnano-particles being homogenously dispersed within a moisture sensitivemicroparticle, said microparticle is formed of a moisture sensitivematrix material and a bioadhesive material surrounding said core or abioadhesive material within said moisture sensitive matrix material,said moisture-sensitive matrix material comprises a water soluablesynthetic polymer, water dispersible synthetic polymer, starchderivative, natural gum, polysacchride, protein, hydrocolloid andmixtures thereof.
 2. canceled.
 3. canceled.
 4. canceled.
 5. canceled. 6.The system of claim 1 wherein said water-soluable synthetic polymer isselected from the group consisting of: polyvinyl pyrrolidone, watersoluble cellulose, polyvinyl alcohol, ethylene maleic anhydridecopolymer, methylvinyl ether maleic anhydride copolymer, acrylic acidcopolymers, anionic polymers of methacrylic acid and methacrylate,cationic polymers with dimethyl-aminoethyl ammonium functional groups,polyethylene oxides, water soluble polyamide and polyester and mixturesthereof.
 7. canceled.
 8. canceled.
 9. The system of claim 1 wherein saidbioadhesive material is selected from the group consisting ofbioerodible hydrogels, polyhyaluronic acid, casein, gelatin, glutin,polyanhydride, polyacrylic acid, alginate, chitosan, poly(methylmethacrylate), poly(ethyl methacrylate), poly (butyl methacrylate),poly(isobutyl methacrylate), poly(hexl methacrylate), poly(isodeclmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), and poly(octadecl acrylate), poly(fumaric-co-sebacic)acid andmixtures thereof.
 10. The system of claim 1 wherein said bioadhesivematerial is a polymer comprising anhydride monomers or oligomers. 11.The system of claim 1 wherein said first active agent is a sensorymarker of a flavor or cooling agent.
 12. The system of claim 11 whereinsaid cooling agent is selected from the group consisting of: menthol,non-volatile menthol analogs, menthyl lactate, menthyl ethoxyacetate,menthone glycerinacetal, 3-1-menthoxypropane-1,2-diol, ethyl 1-menthylcarbonate, (1S,3S,4R)-p-menth-8-en-3-ol, menthyl pyrrolidonecarboxylate, N-substituted-p-menthane-3-carboxamide,N-ethyl-p-menthane-3-carboxamide, N,2,3-trimethyl-2-isopropylbutanamide,ketal coolants, 1-menthon-1d-isomenthon glycerin ketal,3-1-menthoxypropane-1,2-diol, N-ethyl-p-menthane-3-carboxamide,N,2,3-trimethyl-2-isopropylbutanamide, menthyl lactate, menthoneglycerinacetal and menthyl ethoxyacetate.
 13. The system of claim 1wherein said first active agent is a nutraceutical component selectedfrom the group consisting of: antioxidants, phytochemicals, hormones,vitamins, Vitamin A, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12,Vitamin C, Vitamin D, Vitamin E, Vitamin K, pantothenate, folic acid,pro-vitamins, minerals, calcium, selenium, magnesium salts, iron, ironsalts, microorganisms, bacteria, lactobacilli, fungi, yeast, prebiotics,probiotics, unsaturated fatty acids, omega-3 fatty acids, mid-chaintriglycerides, nutritional supplements, enzymes, amylases, proteases,lipases, pectinases, cellulases, hemicellulases, pentosanases,xylanases, and phytases, pigments, oligopeptides, dipeptides, aminoacids and mixtures thereof.
 14. The system of claim 1 further comprisingone or more of an amphoteric surfactant, non-ionic surfactant andcationic surfactant.
 15. The system of claim 1 wherein said moisturesensitive matrix comprises a second active agent, said second activeagent being the same or different as said first active agent, saidmoisture sensitive matrix material releases said second active agentupon contact with moisture and continuously thereafter for an extendedperiod of time.
 16. The system of claim 15 wherein said second activeagent is a first flavor and said first active agent is a second flavor,said first flavor being different than said second flavor whereinrelease of said first flavor and said second flavor provides anorganoleptic perception of a flavor transition.
 17. The system of claim14 wherein said second active agent is a sensory marker of a flavor orcooling agent.
 18. The system of claim 16 wherein said cooling agent isselected from the group consisting of: menthol, non-volatile mentholanalogs, menthyl lactate, menthyl ethoxyacetate, menthoneglycerinacetal, 3-1-menthoxypropane-1,2-diol, ethyl 1-menthyl carbonate,(1S,3S,4R)-p-menth-8-en-3-ol, menthyl pyrrolidone carboxylate,N-substituted-p-menthane-3-carboxamide,N-ethyl-p-menthane-3-carboxamide, N,2,3-trimethyl-2-isopropylbutanamide,ketal coolants, 1-menthon-1d-isomenthon glycerin ketal,3-1-menthoxypropane-1,2-diol, N-ethyl-p-menthane-3-carboxamide,N,2,3-trimethyl-2-isopropylbutanamide, menthyl lactate, menthoneglycerinacetal and menthyl ethoxyacetate.
 19. The system of claim 15wherein said second active agent is a nutraceutical component selectedfrom the group consisting of: antioxidants, phytochemicals, hormones,vitamins, Vitamin A, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12,Vitamin C, Vitamin D, Vitamin E, Vitamin K, pantothenate, folic acid,pro-vitamins, minerals, calcium, selenium, magnesium salts, iron, ironsalts, microorganisms, bacteria, lactobacilli, fungi, yeast, prebiotics,probiotics, unsaturated fatty acids, omega-3 fatty acids, mid-chaintriglycerides, nutritional supplements, enzymes, amylases, proteases,lipases, pectinases, cellulases, hemicellulases, pentosanases,xylanases, and phytases, pigments, oligopeptides, dipeptides, aminoacids and mixtures thereof.
 20. The system of claim 1 wherein saidnano-particles have an average particle diameter between about 0.01microns and about 10 microns.
 21. The system of claim 15 wherein saidmoisture sensitive microparticle releases an effective amount of saidsecond active agent to provide a burst of said active agent.
 22. Thesystem of claim 20 wherein after said burst of said second active agent,said second active agent is continuously released for an extended periodof time.
 23. canceled.
 24. An oral care product comprising the system ofclaim
 1. 25. A toothpaste suitable for use in oral care comprising thesystem of claim
 1. 26. A chewing gum suitable for use in oral carecomprising the system of claim
 1. 27. A confectionary compositionsuitable for use in oral care comprising the system of claim
 1. 28. Apharmaceutical composition suitable for use in oral care comprising thesystem of claim
 1. 29. A dentifrice composition suitable for use in oralcare comprising the system of claim
 1. 30. canceled.
 31. canceled. 32.canceled.
 33. canceled.
 34. canceled.
 35. canceled.
 36. canceled. 37.canceled.
 38. canceled.
 39. canceled.
 40. canceled.
 41. canceled. 42.canceled.
 43. canceled.
 44. canceled.
 45. A beverage product comprisingthe system of claim
 1. 46. The beverage product of claim 45 wherein saidbeverage product comprises a powdered drink mix or a liquid beverage.47. The beverage product of claim 45 wherein said first active agentcomprises a flavorant, sensory marker or nutraceutical.
 48. The beverageproduct of claim 45 wherein said flavorant is selected from the groupconsisting of: crystalline ingredients, dairy ingredients, spices,natural flavors, artificial flavors, thickening agents, proteincompounds, vegetable gums and combinations thereof.
 49. The beverageproduct of claim 45 wherein said second active agent is a first flavorand said first active agent is a second flavor, said first flavor beingdifferent than said second flavor wherein release of said first flavorand said second flavor provides an organoleptic perception of a flavortransition.
 50. The beverage product of claim 45 wherein saidnutraceutical comprises a nutraceutical component selected from thegroup consisting of: antioxidants, phytochemicals, hormones, vitamins,Vitamin A, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin C,Vitamin D, Vitamin E, Vitamin K, pantothenate, folic acid, pro-vitamins,minerals, calcium, selenium, magnesium salts, iron, iron salts,microorganisms, bacteria, lactobacilli, fungi, yeast, prebiotics,probiotics, unsaturated fatty acids, omega-3 fatty acids, mid-chaintriglycerides, nutritional supplements, enzymes, amylases, proteases,lipases, pectinases, cellulases, hemicellulases, pentosanases,xylanases, and phytases, pigments, oligopeptides, dipeptides, aminoacids and mixtures thereof.
 51. A beverage product comprising the systemof claim 45 wherein said first active agent comprises a flavorant,sensory marker or nutraceutical.
 52. The beverage product of claim 51wherein said flavorant is selected from the group consisting of:crystalline ingredients, dairy ingredients, spices, natural flavors,artificial flavors, thickening agents, protein compounds, vegetable gumsand combinations thereof.
 53. The beverage product of claim 51 whereinsaid nutraceutical comprises a nutraceutical component selected from thegroup consisting of: antioxidants, phytochemicals, hormones, vitamins,Vitamin A, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin C,Vitamin D, Vitamin E, Vitamin K, pantothenate, folic acid, pro-vitamins,minerals, calcium, selenium, magnesium salts, iron, iron salts,microorganisms, bacteria, lactobacilli, fungi, yeast, prebiotics,probiotics, unsaturated fatty acids, omega-3 fatty acids, mid-chaintriglycerides, nutritional supplements, enzymes, amylases, proteases,lipases, pectinases, cellulases, hemicellulases, pentosanases,xylanases, and phytases, pigments, oligopeptides, dipeptides, aminoacids and mixtures thereof.
 54. A controlled release delivery system fordelivery to biological surfaces comprising an oral cavity or mucousmembranes of various tissues, said system comprising: a plurality ofsolid nano-particles, each of said solid nano-particles comprising acore formed of a hydrophobic material said hydrophobic material isselected from the group consisting of natural waxes, regenerated waxes,synthetic waxes, vegetable waxes, animal waxes, mineral waxes,cholesterol, fatty acid esters, fatty alcohols, solid hydrogenated plantoils, hard paraffin, hard fats, cellulose derivatives, biodegradablepolymers, copolymers of lactic acid and glycolic acid, syntheticpolymers, triglycerides and mixtures thereof and an effective amount ofa first active agent contained therein and a bioadhesive positivelycharged surfactant entrapped on a surface of each of said solidnano-particles surrounding said core said positively charged surfactantis selected from the group consisting of straight-chain alkylammoniumcompounds, cyclic alkylammonium compounds, petroleum derived cationics,polymeric cationic materials, polymeric amines, water insolublepolymers, cationic derivatives of polysaccharides and mixtures thereof,wherein the first active agent is an antibacterial agent selected fromthe group consisting of thimerosal, chloramine, boric acid, phenol,iodoform, chlorhexidine, oral antiseptic, beta-lactam antibiotic,cefoxitin, n-formamidoyl thienamycin, thienamycin derivatives,tetracycline, chloramphenicol, neomycin, gramicidin, kanamycin,amikacin, sismicin and tobramycin.
 55. A toothpaste suitable for use inoral care comprising: a controlled release delivery system for deliveryto biological surfaces comprising an oral cavity or mucous membranes ofvarious tissues, said system comprising: a plurality of solidnano-particles, each of said solid nano-particles comprising a coreformed of a hydrophobic material said hydrophobic material is selectedfrom the group consisting of natural waxes, regenerated waxes, syntheticwaxes, vegetable waxes, animal waxes, mineral waxes, cholesterol, fattyacid esters, fatty alcohols, solid hydrogenated plant oils, hardparaffin, hard fats, cellulose derivatives, biodegradable polymers,copolymers of lactic acid and glycolic acid, synthetic polymers,triglycerides and mixtures thereof and an effective amount of a firstactive agent contained therein and a bioadhesive positively chargedsurfactant entrapped on a surface of each of said solid nano-particlessurrounding said core said positively charged surfactant is selectedfrom the group consisting of straight-chain alkylammonium compounds,cyclic alkylammonium compounds, petroleum derived cationics, polymericcationic materials, polymeric amines, water insoluble polymers, cationicderivatives of polysaccharides and mixtures thereof.
 56. An oral rinsesuitable for use in oral care comprising: a controlled release deliverysystem for delivery to biological surfaces comprising an oral cavity ormucous membranes of various tissues, said system comprising: a pluralityof solid nano-particles, each of said solid nano-particles comprising acore formed of a hydrophobic material said hydrophobic material isselected from the group consisting of natural waxes, regenerated waxes,synthetic waxes, vegetable waxes, animal waxes, mineral waxes,cholesterol, fatty acid esters, fatty alcohols, solid hydrogenated plantoils, hard paraffin, hard fats, cellulose derivatives, biodegradablepolymers, copolymers of lactic acid and glycolic acid, syntheticpolymers, triglycerides and mixtures thereof and an effective amount ofa first active agent contained therein and a bioadhesive positivelycharged surfactant entrapped on a surface of each of said solidnano-particles surrounding said core said positively charged surfactantis selected from the group consisting of straight-chain alkylammoniumcompounds, cyclic alkylammonium compounds, petroleum derived cationics,polymeric cationic materials, polymeric amines, water insolublepolymers, cationic derivatives of polysaccharides and mixtures thereof.57. A gel suitable for use in oral care comprising: a controlled releasedelivery system for delivery to biological surfaces comprising an oralcavity or mucous membranes of various tissues, said system comprising: aplurality of solid nano-particles, each of said solid nano-particlescomprising a core formed of a hydrophobic material said hydrophobicmaterial is selected from the group consisting of natural waxes,regenerated waxes, synthetic waxes, vegetable waxes, animal waxes,mineral waxes, cholesterol, fatty acid esters, fatty alcohols, solidhydrogenated plant oils, hard paraffin, hard fats, cellulosederivatives, biodegradable polymers, copolymers of lactic acid andglycolic acid, synthetic polymers, triglycerides and mixtures thereofand an effective amount of a first active agent contained therein and abioadhesive positively charged surfactant entrapped on a surface of eachof said solid nano-particles surrounding said core said positivelycharged surfactant is selected from the group consisting ofstraight-chain alkylammonium compounds, cyclic alkylammonium compounds,petroleum derived cationics, polymeric cationic materials, polymericamines, water insoluble polymers, cationic derivatives ofpolysaccharides and mixtures thereof.
 58. A breath spray suitable foruse in oral care comprising: a controlled release delivery system fordelivery to biological surfaces comprising an oral cavity or mucousmembranes of various tissues, said system comprising: a plurality ofsolid nano-particles, each of said solid nano-particles comprising acore formed of a hydrophobic material said hydrophobic material isselected from the group consisting of natural waxes, regenerated waxes,synthetic waxes, vegetable waxes, animal waxes, mineral waxes,cholesterol, fatty acid esters, fatty alcohols, solid hydrogenated plantoils, hard paraffin, hard fats, cellulose derivatives, biodegradablepolymers, copolymers of lactic acid and glycolic acid, syntheticpolymers, triglycerides and mixtures thereof and an effective amount ofa first active agent contained therein and a bioadhesive positivelycharged surfactant entrapped on a surface of each of said solidnano-particles surrounding said core said positively charged surfactantis selected from the group consisting of straight-chain alkylammoniumcompounds, cyclic alkylammonium compounds, petroleum derived cationics,polymeric cationic materials, polymeric amines, water insolublepolymers, cationic derivatives of polysaccharides and mixtures thereof.59. A method for treating periodontal disease comprising inserting intoa periodontal pocket; a controlled release delivery system for deliveryto biological surfaces comprising an oral cavity or mucous membranes ofvarious tissues, said system comprising: a plurality of solidnano-particles, each of said solid nano-particles comprising a coreformed of a hydrophobic material said hydrophobic material is selectedfrom the group consisting of natural waxes, regenerated waxes, syntheticwaxes, vegetable waxes, animal waxes, mineral waxes, cholesterol, fattyacid esters, fatty alcohols, solid hydrogenated plant oils, hardparaffin, hard fats, cellulose derivatives, biodegradable polymers,copolymers of lactic acid and glycolic acid, synthetic polymers,triglycerides and mixtures thereof and an effective amount of a firstactive agent contained therein and a bioadhesive positively chargedsurfactant entrapped on a surface of each of said solid nano-particlessurrounding said core said positively charged surfactant is selectedfrom the group consisting of straight-chain alkylammonium compounds,cyclic alkylammonium compounds, petroleum derived cationics, polymericcationic materials, polymeric amines, water insoluble polymers, cationicderivatives of polysaccharides and mixtures thereof.